Lung inflammation is characterized by the massive infiltration of activated white blood cells (WBCs) in the lung and airway subsequent to many immune related causes. Although some treatments are available to treat the underlying disease, many of these diseases do not have a cure and are chronic diseases, or the treatment for the disease is not immediately effective, and the resulting lung inflammation remains a health concern for the patient. Steroids are used as an adjunct therapy to treat lung inflammation, however the chronic use of steroids often leads to multiple side effects such as proximal myopathy, cushingoid habitus, hyperglycemia, diabetes, infections and osteoporosis. Other drugs are known to down regulate the immune system, but many of these drugs are unable to differentiate between resting and activated immune cells, and generally have a potent immunosuppression effect. Thus, there is a need for new treatments to reduce lung inflammation caused by many diseases and immune related disorders, with minimal immunosuppression and associated side effects.
In lung related disorders, various subtypes of WBCs show up-regulation and activation of Lymphocyte function-associated antigen 1 (“LFA-1”). The activated LFA-1 then mediates the migration of WBCs into the airways. Once migrated, the inflammatory WBCs cause airway inflammation and bronchial remodeling that can lead to adverse effects in a subject if the inflammation is uncontrolled.
Lung inflammation is a general term for inflammation affecting any part of the lung or surrounding tissue and fluid, and the up-regulation of certain cytokines. Clinical characteristics of lung inflammation may include shortness of breath, increased fluid and/or mucus in the lungs, increased coughing, associated pain when breathing and inability to breathe. The treatment for lung inflammation is aimed at reducing inflammation and the associated clinical symptoms caused by uncontrolled lung inflammation.
Agents that target LFA-1 have been used to treat asthma, a chronic disorder that causes lung inflammation, including, for example, simvastatin, a small molecule drug that can target LFA-1, and efalizumab, a monoclonal antibody against LFA-1. In randomized controlled trials of asthma patients, simvastatin was shown to reduce airway and sputum eosinophilia, but it did not affect airway hyperresponsiveness or reduce the expression of inflammatory cytokines (IL-4, 5) compared to the placebo. Treatment of asthma patients with efalizumab, by blocking LFA-1 caused while the drug is bound to the receptor, caused a decrease in the number of inflammatory cells as well as a decrease in the late airway response compared to placebo, but it did not have any effect on the early asthmatic response.